Trabecular bone adaptation plays a significant role in the etiology of many metabolic bone diseases such as osteoporosis and osteopetrosis, bone loss in microgravity, and the long term success or failure of porous implants in total joint arthroplasty. Parathyroid hormone (PTH) is an important anabolic agent when administered intermittently. We have developed a novel in vivo rat-tail vertebra model coupled with an uCT image based finite element technique. Specifically, a controlled mechanical load can be applied to a rat-tail vertebra and a detailed three-dimensional (3D) stress/strain environment in the trabecular bone tissue can be determined using an advanced finite element microstructural model. In this proposal, we designed a full-scale, long-term study to systematically quantify the molecular/cellular responses and changes in 3D morphology in trabecular bone to combinations of mechanical loading and PTH treatment. The molecular responses will be assayed using RT-PCR and in situ hybridization. The bone cellular response will be quantified using bone histomorphometric techniques. The specific aims of this project are: Specific Aim 1: To determine the changes in gene expression (c-fos, cbfa-1, IGF-1, collagen a1(I), osteopontin, osteocalcin, alkaline phosphatase, RANK-L, and osteoprotegerin) by RT-PCR and in situ hybridization, bone cell activities by bone histomorphometry, and 3D trabecular bone morphology by uCT of rat tail vertebrae at various levels of mechanical loading (ON, 50N and lOON) ranging from 1 day to twelve weeks. Specific Aim 2: To determine the changes (using the same measurements cited in Specific Aim 1) in rat-tail vertebrae in response to daily PTH administration (3O-ug/kg and 6Oug/kg) for various lengths of time. Specific Aim 3: To determine the changes (using the same measurements cited in Specific Aim 1) in rat tail vertebrae mechanically loaded at various magnitudes (ON, SON, and lOON) in the presence of PTH (30ug/kg and 6O ug/kg) for various lengths of time. Specific Aim 4: To perform uCT based PEA of the loaded vertebrae in Specific Aims 1 and 3, and to determine the changes in the distribution of trabecular bone tissue stress/strain parameters following the various treatments. Results from this study will help to clarify, in a quantitative manner, the cellular and molecular mechanisms of bone adaptation to mechanical loading, which are important in the understanding of the etiology and optimizing therapeutic interventions of menopausal, microgravity or age related osteoporosis, and improvement in total joint replacements.